title: Activation of c-Src and Fyn kinases by protein-tyrosine phosphatase RPTPalpha is substrate-specific and compatible with lipid raft localization.
abstract: Src family tyrosine kinases (SFKs) function in multiple signaling pathways, raising the question of how appropriate regulation and substrate choice are achieved. SFK activity is modulated by several protein-tyrosine phosphatases, among which RPTPalpha and SHP2 are the best established. We studied how RPTPalpha affects substrate specificity and regulation of c-Src and Fyn in response to epidermal growth factor and platelet-derived growth factor. We find that RPTPalpha, in a growth factor-specific manner, directs the specificity of these kinases toward a specific subset of SFK substrates, particularly the focal adhesion protein Paxillin and the lipid raft scaffolding protein Cbp/PAG. A significant fraction of RPTPalpha is present in lipid rafts, where its targets Fyn and Cbp/PAG reside, and growth factor-mediated SFK activation within this compartment is strictly dependent on RPTPalpha. Forced concentration of RPTPalpha into lipid rafts is compatible with activation of Fyn. Finally, RPTPalpha-induced phosphorylation of Paxillin and Cbp/PAG induces recruitment of the SFK inhibitory kinase Csk, indicative of negative feedback loops limiting SFK activation by RPTPalpha. Our findings indicate that individual SFK-controlling PTPs play important and specific roles in dictating SFK substrate specificity and regulatory mechanism.
authors.affiliation: Biotech Research and Innovation Center, Copenhagen Biocenter, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vacaresse
authors.forename: Bente
authors.initials: B
authors.lastname: Møller
authors.forename: E Michael
authors.initials: EM
authors.lastname: Danielsen
authors.forename: Masato
authors.initials: M
authors.lastname: Okada
authors.forename: Jan
authors.initials: J
authors.lastname: Sap
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016391:Genes, src / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051419:Paxillin / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity / Q000187:drug effects / Q000502:physiology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C408344:Pag protein, mouse; D051419:Paxillin; D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; C496062:Pxn protein, mouse; D004815:Epidermal Growth Factor; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; C516843:Ptpra protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4